The purpose of the proposed research is to investigate the molecular mechanisms responsible for alcohol, barbituarte and opiate intoxication and dependence. Particular emphasis will be placed on the role of brain-membranes and calcium in these phenomena. Biophysical studies utilizing fluorescent probe molecules will monitor specific microenvironments of brain membranes, while differential scanning calorimetry, which measures bulk properties of membranes, will complement the more sensitive fluorescent probes approach. Specifically, alterations in fluidity, fluidity gradients, phase transitions, and surface charge will be monitored in response to acute and chronic administration of alcohol, baribiturates and opiates to experimental animals. These investigations will be correlated with biochemical studies evaluating the effects of these drugs on the lipid composition of brain membranes. In addition, genetic differences in the development of tolerance and dependence by different strains of mice will be used to evaluate the behavioral significance of the biochemical and biophysical findings.